TWI314453B - Novel polygalatenosides and use thereof as an antidepressant agent - Google Patents
Novel polygalatenosides and use thereof as an antidepressant agent Download PDFInfo
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- TWI314453B TWI314453B TW095140267A TW95140267A TWI314453B TW I314453 B TWI314453 B TW I314453B TW 095140267 A TW095140267 A TW 095140267A TW 95140267 A TW95140267 A TW 95140267A TW I314453 B TWI314453 B TW I314453B
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- 208000011580 syndromic disease Diseases 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical group N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- POOSGDOYLQNASK-UHFFFAOYSA-N tetracosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC POOSGDOYLQNASK-UHFFFAOYSA-N 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 150000007964 xanthones Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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Description
1314453 •九、發明說明： • 發明所屬之技術領域 本發明涉及新的遠志齡苦（polygalaten〇sides)，其由遠 志的水溶性萃取物純化得到，也涉及它們作為抗 抑鬱藥物的用途。 & 先前技術 Φ 近年來，精神疾病例如焦慮和神經症的患病率增加， 目前多種抗抑鬱藥物對其治療有效。大量的研究證實較新 的抗抑鬱劑，例如文拉法辛（去甲腎上腺素重攝取抑制劑） 和丁氨苯丙酮（去甲腎上腺素/多巴胺重攝取抑制劑）通過與 中栖神經系統内的多種受體相互作用而發揮作用。 • 遠志（Yuan Zhi)”（户吻容心以㈣_/ο/ζ·α Willd的根， 遠志科）為傳統中醫藥中規定的重要草藥，其對中枢神經系 統作用而產生調節鎮靜、抗精神病、認知改善、神經元保 • 護和抗炎治療效果。也已經將其用於失眠症、神經衰弱症、 健忘症、帶有焦慮症的心悖、坐立不安、定向障礙和用於 預防癡呆和記憶減退。已經報導多種夾氧雜蒽酮類、皂苷 類和低聚糖酯類來自這種植物。[Fujita,T.; Liu，D. Y.; Ueda， S.; Takeda, Y. Phytochemistry 1992, 31, 3997-4000; Ikeya, Y·； Sugama, K.; Okada, M.; Mitsuhashi, H. Phytochemistry 1991, 30, 2061-2065; Ikeya, Y.； Sugama, K.; Okada, M.; Mitsuhashi, H. Chem. Pharm. Bull. 1991, 39, 2600-2605; Miyase, T.； Iwata, Y.; Ueno, A. Chem. Pharm. Bull. 1991, 39, 1314453 3082-3084; Jiang, Y.; Tu, P. F. Phytochemistry 2002, 60, 813-816; Sakuma, S.; Shojji, J. Chem. Pharm. Bull. 1981, 30, 810-821; Jiang, Y.;Tu, P. C/iem. P/zarm. 5w//. 2005, 53, 1164-1166; Jiang, Y.; Tu, P. J. Asian Nat. Prod. Res. 2003, 5, 279-283; Jiang, Y.; Zhang, W.; Tu, P. Xu, X. J. Nat. Prod. 2005, 68, 875-879.] GB238395 1A公開了一種抗抑鬱藥物組合物，包含治療
有效量的活性成分和用於該活性成分的可藥用載體或稀釋 劑的混合物’其中活性成分為i)遠志（Pobga/a)的極性溶劑 萃取物’所述極性溶劑為水和曱醇或乙醇的混合物；u)用 有機溶劑萃取極性溶劑萃取物得到的含水部分；iU)將極性 溶劑萃取物或含水部分引入到反相層析柱，用水和有機溶 劑溶離得到有機溶離液；或iv)從有機溶離液中過濾得到分 子量小於30000道爾頓的濾出液。 美國專利No. 6,642,235公開了用於 "T、〜0 -工讲 π 或精神疾病、紊亂或其中抑制去曱腎上腺素的重攝取為^ 益的病症的患者或預防人們患有上述疾病的方法和組合 物。所述生S疾病或精神疾病、|亂或病症選自成癩性承 病（addictive dis〇rders)(包括由乙醇、煙驗和其他精神活十 物質引起的那些）和戒斷综合症、適應、性障礙（包括情感伯 洛、焦慮症、混合的焦慮症和情感低落、行為紊亂和混^ 的行為純和情感低幻、年齡相關的認知障礙和精神障: (包括阿ϋ茨海默病）、神經性厭食症、情感淡漠、由^ 的醫療行為引起的注意力缺陷（或其他的認知）障礙、注邊 1314453 缺陷障礙多動症（ADHD)、雙相性精神障礙、神經性貪食 症、慢性疲勞綜合症、慢性或急性應激、慢性痛、行為障 礙迴圈情感性精神障礙（cyclothymic disorder)、抑繫（包 • 括青春期抑鬱和輕性抑鬱）、情緒惡劣、纖維肌痛和其他的 軀體病樣精神障礙（包括軀體化障礙、轉換障礙、疼痛障礙 (Pain disorder)、臆想症、軀體變形障礙、未分化的軀體形 式障礙和軀體形（somatof〇rm )N〇s)、泛化性焦慮症 • (GAD)、失禁（即壓迫性（尿）失禁、真性壓迫性（尿）失禁和混 合的失禁）、呼吸障礙（inhalation disorders)、中毒性疾病 (uit〇xication dis〇rders)(酒精成瘾）、躁狂症、偏頭痛、肥胖 •症(即降低肥胖或超重患者的體重，強制性障礙和有關的譜 群疾病、對立違抗性障礙、驚恐障礙、外周神經病、創傷 後精神緊張性（精神）障礙、月經前焦慮障礙（即月經前期綜 σ症和晚期育體期煩躁不安的紊亂）、精神障礙（包括精神 刀裂症、情感分裂和精神分裂症樣的紊亂）、季節性情感障 礙、睡眠障礙（例如發作性睡眠和尿失禁）、社交恐怖症（包 括社交焦慮障礙)、特定性發育障礙、選擇性五經色胺重攝 取抑制（順）“批發（po〇p〇ut)”、综合症（即，其中在最初的 滿意應答期後，患者很難保持對s s R1 _治療的滿意應答）和 TIC紊亂（例如圖雷特氏病）。 發明内容 目的是提供新的遠志酚普。 的是提供本發明的新遠志酚苷 的抗 本發明的一個主要 本發明的另一個目 1314453 抑鬱藥物用途。
在本發明中，研穿了、责士 rD 取物的曱醇溶離液f+fl25 f生卒 又對[I]RTI-55[3M4_蛾苯基 -2β-羧酸曱酯]-膜蛋白 ^ 白夤、、、σ 5的抑制作用。本文中， 導了生物測定指導分離……。 找們報 離（ioassay-gU1ded separati〇n)由遠士 i25 低欵糖何生物（1_5)，發現其可抑制 [I]RTI 55與去曱腎上腺素運載體（下文中簡稱為NET) 蛋白的結合。發現其中的化合物1和2比其他的化合物更 有效。 實施方式 本發明提供具有下式的遠志酚苷或其可藥用鹽：
包含其光學活性的化合物的消旋混合物或光學純R和 S立體異構體， 其中R、R，和R”獨立地為幵或心，前提是R、R，和 R"不能都為Η，其中R!為 1314453
Cl_C6烷氧基或 Η。 鹵素 其中R2為氫、C1-C6烧基、 優選地，R2為氫。 優選地，R為&，R"為
優選地’ R，為R,，r和R"為η 優選地，R"為R!，尺和R，為Η
本發明還提供抗抑鬱藥 效量的作為活性成分的如上 鹽’與用於所述活性成分的 本發明還提供如上式定 1備治療患有抑鬱的患者的 本發明還提供如上式定 製備治療患有其中抑制了去 物中的應用，其中遠志酚苦 素重攝取抑制劑，阻斷了去 奶組合物，包含抗抑 式疋義的遠志酚苷或其可藥用 可藥用載體或稀釋劑的組合。 義的遠志酚苷或其可藥用鹽在 藥物中的應用。 義的遠志酚苷或其可藥用鹽在 甲腎上腺素重攝取的患者的藥 或其可藥用鹽作為去甲腎上腺 甲腎上腺素的輸送。 優選地，所述的疾病為成癌性障礙、戒斷综合症、適 應性障礙、年齡相關的認知障礙和精神障礙、神經性厭食 症、情感淡漠、注意力缺陷障礙、注意缺陷障礙多動症 (ADHD)、雙相性精神障礙或肥胖症。 [125I]RTI-55-膜結合測定指導分劃（fracti〇nati〇n)和分 離（separation) ·〇//α根的水溶性萃取物得到 10 1314453 "了五種新的低聚糖衍生物，遠志酚苷A-E (l-s)。u * * •柄a 、 延些新的 低聚糖的結構是以光譜證據為基礎 — ^ 牡砀膜結合測 疋，遠志酚苷A和B (1和2)顯示了顯著的抑制活性， 1匸5〇值分別為3〇_〇和6.04 μΜ，並通過阻斷去曱腎上腺素 的運輪而起去甲腎上腺素重攝取抑制劑作用。 試驗： 常規試驗步驟。用JASCO DIP-370 P〇larmeter記錄旋 φ 光度。用Hitachi UV-3210分光光度計記錄uv光譜。用 JASCO IR Report_100分光光度計做KBr discs測定IR光 譜。採用 Cosmosil 5C-18-MS-II 管柱（20 X 250 _ 和 4 6 χ 250 mm, 5 μιη)的 Shimadzu LC-10ATKiJ (Japan)系統進行
HPLC。用 Bruker AMX-400 和 Varian-400 Unity Plus NMR - 光譜儀記錄1H、13C、HMQC、HMBC 和 NOESYNMR 光譜， 使用四曱基矽烷（TMS)作内標物；所有的化學位移記錄為百 萬分率（ppm，0。用VG 70-250 S光譜儀測定質譜（EI或 φ FAB)。 植物原料。遠志（P. 的根於2003年5月購自 臺北的市場’由郭長生副教授（國立成功大學生命科學系） 鑒定。植物的憑證標本（No. 920021)保藏在臺灣臺北縣的財 團法人醫藥工業技術發展中心的植物標本室。 萃取和分離。將遠志（1.25 kg)的風乾的根製成粉末， 用H20 (5 L)迴流萃取兩次，每次2小時。H20萃取物上 Diaion HP-20 柱層析，用 h20 (45 L)、50% MeOH (30 L) 和MeOH (2 5 L)連續溶離。減壓濃縮50% MeOH溶離物， 11 1314453 '得到淺黃色（pale yellow)糖漿（44 g)，上矽膠柱（2〇3_4〇〇 .mesh，E. Merck, 800 g)進行層析分析，溶離液為 CHCl3/MeOH (80:20, 75:25, 70:30, 65:35 和 50:50)和 1〇〇% 曱醇’得到六種分劃。使用H^/CH/N作為流動相（h2〇: CH3CN = 70 : 30，流速：1〇 mL/min; UV 230 nm)，經製備 HPLC [ODS-5 (20 X 250 mm)]分離分劃 2 (1·〇 g)，得到三種 mg) ’ 5 (滯留時間：17 7分產 min) (3 時間： 亞分劃：2-1 (125.3 mg)，滯留時間為5_13分鐘；2_2 (121 3 • mg)，滯留時間為I3·18分鐘，和2-3(27.lmg)，滞留時間 為18-23分鐘。上肌c管柱：〇DS_5 (4 6 χ 25〇叫分離 亞分劃2-2，流動相為H2〇_Me〇H (8〇:2〇);流速^ 〇心 分鐘；UV:23〇nm]，分別得到2(滞留時間：13 3min)(3」 .17.7分鐘）（1 6 mg)，4 (滯留時間：
12 1314453
0 OH HO
O CH2OH 1R = H，R' = H,R"=苯曱醯基 2 R =苯甲醯基,R' = H, R" = Η 3 R = H，R'=笨甲醯基,R” = Η hoh2c HO^ HO hoh2c 0 0-- T— HO Cl 4
(2009年7月修正） och3 h3co hoh2c hoh2c
HO OH 5 遠志盼苷 A (1):無色糖漿，+171 〇 0.01, MeOH); UV (MeOH) Xmax (log ε) 228 (4.12), 273 (3.41), 279 (sh) • (3.37) nm; IR (KBr) vmax 3411, 1713, 1634, 1603, 1585, 1285, 1080 cnT1; 4和 13C NMR,參見表 i和 2; FABMS m/z 431 ([M + H] + , 3), 307 (40), 291 (24), 289 (18), 267 (8), 154 (100), 139 (1 1), 138 (28), 137 (56), 136 (58), 107 (15); HRFABMS w/z 43 1.1 557 [M+l]+ 理論值：43 1.15 53)。 遠志酚苷B (2):無色糖漿，[a]D +343.1 〇 0.003， MeOH); UV (MeOH) Imax (log ε) 228 (3.94), 272 (3.69) nm; IR (KBr) vmax 3415, 2927, 1713, 1602, 1452, 1280 cm'1; 和 13C NMR，參見表 1和 2 ; FABMS m/z 43 1 [M + H] + , 307, 13 1314453 291, 289, 154, 137, 136, 107; HRFABMS m/z 43 1.1552 • [M+l]+ 理論值：43 1.1 553)。 遠志酚苷C (3):無色糖漿，[a]D +256.6 (c 0.005， MeOH); UV (MeOH) λιη&χ (log ε) 229 (3.87), 273 (3.72), 301 (3.5 5) nm; IR (KBr) vmax 3 402, 1713, 163 1, 1602, 1452, 1280 cnT1; 4和 13C NMR，參見表 1 和 2 ; FABMS m/z 43 1 ([M + H] +，3.4), 307 (33)，291 (21)，289 (15)，267 (8)，155 (27)， 鲁 154 (100), 139 (1 1), 138 (29), 137 (57), 136 (61), 107 (16); HRFABMS m/z 43 1 · 1 5 54 [M+1 ]+ (C ,的理論值： 431.1553) ° 遠志酚苷D (4):無色糖漿，[a]D +103.7 (c 0.004， MeOH); UV (MeOH) Xmax (log ε) 216 (3.98), 258 (4.02) nm; - IR (KBr) vmax 3414, 1708, 1606, 1512, 1464 cnT1; 4 和 13C NMR，參見表 1和 2 ; HRFABMS m/z 477.1606 [M+l] + ((：2〇1129013 的理論值：477.1611)。 • 遠志酚苷Ε (5):無色糖漿，[a]D +616.8 〇 0.001，
MeOH); UV (MeOH) Xmax (log ε) 258 (4.15) nm; IR (KBr) vmax 3400，1 585，1505，1464, 1405 cm·1; 4和 13C NMR，參 見表 1和 2 ; FABMS m/z 5 05 ([M + H] +，0.5)，5 03 (2)，45 9 (3)， 371 (3), 369 (3), 297 (4), 277 (11), 241 (16), 185 (100), 149 (28), 1 17 (10), 93 (98), 75 (40); HRFABMS m/z 505.1920 [M+l]+ ((：221133013 的理論值：505.1923)。 膜結合測定。使用來自狗腎MDCK細胞的膜，其穩定 地轉染去甲腎上腺素運載體。在500 cm2組織培養m中從 14 1314453 生長融合的轉染細胞製備全部的細胞膜。將細胞刮取至離
-心管中，在9〇〇g和4。〇下離心1〇分鐘製成糰粒。將該糰 粒（pellets)再懸浮在改性的Tris_Hcl緩衝液f(5〇mM Tris-HC卜100 mMNaC卜1 μΜ抑（蛋白）酶醛肽、1〇 _ PMSF、PH7.4)，在17000 g和代下離心30分鐘。然後， 再懸浮該糰粒，用含有Teflon研棒的玻璃勻聚器句化在 1 7000 g和4°C下離心90分鐘。收集固體粒，再懸浮在改性 φ 的Tris_HC1缓衝液中。使用BCA蛋白測定試劑（pierce， Rockford)測定蛋白質濃度。進行結合試驗時，用〇 2 nM
[i]Rti_55 [3β-(4·蛾苯基）_霞菪烧_2β_叛酸曱酉旨]在下 與40 膜蛋白培育3小時。随後經Whatman GF/B的快速 • 真空過濾使結合終止，並以冰冷的缓衝液中進行三次快速 - 洗滌（每次1 ml)。用γ發射光譜測定結合放射性。在存在 10 μΜ地昔帕明（desipramine)下測定非特異性結合，並減 除不存在地昔帕明下的資料，得到特異性結合。 _ 結果： 將風乾的遠志的根製成粉末，用水迴流萃取。水萃取 物上Diaion HP-20柱層析，依次用h20、50%含水MeOH 和100% MeOH溶離。將50%含水MeOH溶離液上矽膠柱， 使用CHCU-MeOH溶離，得到六個分劃。其中，分劃2以 濃度相關的方式抑制[125I]RTI-55與MDCK細胞中去曱腎 上腺素運載體的結合。計算IC5〇值為4.6 pg/mL。然後將分 劃2注入於製備型HPLC，使用反相（ODS)管柱，分離出五 種新的低聚糖衍生物，遠志酚苷A-E (1-5)。 15 1314453 分離的遠志酚苷A(l)為無色糖漿。1的HRFABMS顯 示出質子化的分子離子峰為w/z 43 1.1557 [M+H]+，分子式 為C i。UV光谱顯不的吸收最大值表明存在笨曱酿
基殘基。IR光譜中，3411和1713cm-1的譜帶顯示存在羥 基和共軛的酯羰基。〖H NMR光譜顯示苯曱醯基的信號（δ 7.99,2Hd·’ 7.61，lH，t; 7.47, 2H，d)以及由半乳糖基和遠 志醇基（polygalitosyl)殘基產生的信號（表〇。而且，由笨 甲醯基、半乳糖基和遠志醇基部分產生的nc NMR信號（表 2)也指出1為苯曱酸的遠志醇基半乳糖苷。所有的質子和 碳NMR信號也可以由ϋ COSY、HMQC和HMBC丽R 試驗歸屬。與遠志醇（p〇lygalit〇1)的c_2低磁場位移 (d〇wnfield shift)相比，遠志醇基單元的低磁場位移為4 和半乳糖基單元的c-i的低磁場位移為Sc 95 7，表明在1 中的糖普鍵内的連接為遠志醇基^^半乳糖芽。這可 通過HMBC試驗（圖υ中的半乳糖基單元的^和遠志醇 部分（δ<： 73.3)的C-2之間的3j關仫峨每 ’』幻J關係證實。在NMR光譜中， 半乳糖殘基的亞甲基質子传祙& & , 丫丞貨于乜號的低磁場位移為心4 49和 4.39，它的 C-6 碳為 δ。64 3， J ’疋本甲醯基在C-6位置 連接。這可由Η-6 (δΗ4.49和4 39仏贫田祕w α μ 也 9)和本甲醯基的酯羰基碳 (3C 168.2)證實。對所有現右皆 过川… 現有貪枓的分析使我們得出遠志酚 普A⑴為6_〇_苯甲醢基遠志醇基-(2_^_心半乳糖。 分離的遠志紛普B(2)和c(3)為無色 HRFABMS得到的質子化 矛3的 刀卞離子峰分別在 和 431.1554 [M+H] +，它們的 upiVTA m/z^\A552 們的CNMR資料分子式C19H26〇11 16 1314453 ，一致，與1的結構類似。每個ϋν光譜顯示的最大吸收對 應於苯甲醯基殘基。在34丨5和1713 cm.1的IR譜帶表明分 別存在羥基和共軛的酯羰基。遠志酚苷B和c的nmr光 。曰刀別與1的結構類似，顯示作為酯基部分的苯甲醯基殘 基，作為糖基部分的半乳糖基和遠志醇基殘基。這些殘基 的取代可以在所有來自ih_ih c〇SY和HMQC光譜的質子 仏號歸屬之後在NOE (圖2)和HMBC (圖1) NMR觀察的輔 % 助下來確定。存在兩個化合物2和3的13CNMR譜中的遠 志醇基的C-2和半乳糖基部分的ca的低磁場位移信號以 3及HMBC光譜中H-1 (半乳糖基）和c_2(遠志醇基）之間的 3j關係的存在證實了糖基為遠志醇基-Q—D-a-半乳糖苷， 與1中的相同。然而，發現這些化合物在酯鍵連接上不同。 在2中，半礼糖基單兀的h_3和c_3信號的低磁場位移分 另J為δΗ 5.29和δ(： 75.3，表明苯甲醯位於半乳糖殘基的c_3 上。在3中，半乳糖基中的H_4和c_4的信號的低磁場位 移分別S δΗ 5.59和δ。73.5，表明苯甲醯基連接於半乳糖 基C-4。适可得到HMBC光譜中半乳糖基單元H_4 (h 5 59) 和苯甲醯基C_7 (δ(： 167.9)幾基碳之間的ν關係的證實。 因此，2被確定的結構為3 _〇_苯甲醯基_遠志醇基_(2—〖）_α_ 半乳糖，3為4_〇_苯甲醯基-遠志醇基_(2 —1}_α_乳糖。 得到的遠志酚苷D(4)為無色糖漿。HRFABMS顯示了 質子化的分子離子峰w/z 477.16〇6，相應的分子式為 c2〇h29o13Q4的uv光譜顯示在216和258 nm有吸收。在 3414和1708 cm-i的以譜帶與存在羥基和共椀的醋羰基一 17 1314453 •致° H NMR光譜顯示A2B2類型的芳香質子的信號（δ 8.06 和7.01 ’每個為2Η)，和甲氧基信號（δ 3 86, 3H，s) ’以及 屬於蔗糖部分的信號。4的13C NMR光譜也顯示出屬於對 甲氧基苯甲醯基和蔗糖殘基的信號（表2)。通過COSY、 HMQC和HMBC試驗確定了所有的ιΗ和13C NMR信號 的歸屬。果糖基部分的氧亞甲基質子和碳（H_3和c_3)分別 存在的低磁場位移為δΗ 5_56和80.6，表明對甲氧基苯 春甲酿基部分位於4的C-3'上。這可得到HMBC光譜的證實， 因為果糖基殘基的Η-3 (δΗ 5.56)與在3C 167.7的對甲氧基 笨甲醯基的醋羰基碳相關。因此，推斷4的結構為3 〇_ #严輿差苯曱醯基-蔗糖。 分離的遠志酴苷E (5)為無色糖漿，根據其HRFABMS '([M+H]+w/z 505.1920)推斷其含有基本組合物C22H32〇13 〇 IR吸收帶為3400、1585、1505和1464 cm·1，表明存在羥 基和芳香部分。5的NMR資料顯示出廣4· _芥子醇部分信 • 號，其包括兩個相同的芳香質子δΗ 6.55 (2H，s)、兩個甲氧 基δΗ 3·83 (6H，s)、兩個順式_烯鍵質子& 6 48 (1H，本j = 11.6 Hz)和 5.80 (1H，dt，11_6, 6.4 Hz)，和氧基亞甲基 質子 δΗ 4.3 4 (2H，dd，J = 6.4, 1.6 Hz)，以及 5 的 13匸 nmr 光譜中葡萄糖基的103. 2、79.2、79.2、71.8、78 5和 63.1的信號和芹菜糖基（叩丨〇^1)的δ<：：11〇9、786、4、 76.1 和 66.9 h 號0 根據 kalopanaxin D [Kazuko, S·. Shuichi S.; Yoshiteru I.； Junzo, S. Chem. Pharm. Bull. 1991 3g 865-870]來比較這些資料，推斷糖部分為卜序菜糖基 18 1314453 -(1->2)-β-糖苷部分。這得到了 HMBC試驗中（圖1)的葡萄 糖基的C-2低磁場位移至δ(： 79 2和葡萄糖基單元的 質子（δί1 3·69)與芹菜糖基（5C 110.9)單元的C-1之間的3j 關係的證實。而且’根據對葡萄糖基(δίί 510)和順式_ 芬子基（slnapyl)C-4(δc135.5)之間觀察的HMBC相互關係 為基礎，發現芥子醇位於葡萄糖基C-1。根據這些資料， 推斷5的、结構為界子醇4_〇_卜芽菜糖基葡萄糖。 體外測定化合物1-5抑制同位素標記的rti_55結合到 去甲腎上腺素運載體蛋白的能力[GaUi，A.; Defelice L_ J·;
Duke’ B. I.，M〇0re，K R ;礙❸，Rm印⑽ I% : 212]。在該膜結合測定中，遠志酚苷入（1)和B (2、
顯示了顯著的抑告丨、、去w T„ .. _ J 性，1C5。值分別為30.0和6.04μΜ。 曰日，—種三環抗抑鬱藥，也抑制[m NET，ΤΓ 括 * 丨〜L 1JRTI-55 結合 π值為0.93 nM。這些結果表明… 地阻斷NETs而起去 可以通過特定 (去甲月上腺素重攝取抑制劑的作用。 19 1314453 τι· 实觫 ϋ^ΉΪΑΙΜ ΚΙ^ψαο-αυ-^ιτϊ-ϊ ·ϊ< Λ (ιη·^$.(ΝΙ)ρρ09.ε (ιη·π)ρ98·Γη ((Nv?) ΐφΓηΓε (<Ν-ί8) ρρ<Νε·ε (ς·°°.π)ρρ Ις·ε 5I)PST (Il)i-e (lnd)PPH·寸 (SP Α5.ε §ρ/^·ε (Γιη) u 寸.寸 S.Jq (s V6)PP05 (5·εβ·6)ρρ 寸 6.ε (ιο·Γη)τ360·9 OZ： (9 ΚΙ)ρρ?ε (3I)P9ST (96ρρ(ΝΓε δϊΓηε.ε (6)12 (looc) Ρί 89Τ (6d)pporcn 5Ι)ρρα·寸 (9-is) ΡΡ<Ν卜·ε (9-TS) ρροο卜·ε (9) m.寸 •Jqlnr 寸 (ιητ-ίΟΙ)ρρ 6Γ»η (i/-i0I)PPI<N> (寸)匁95 日£0>1-歡妨概 日6ε_寸 曰6寸·寸 9 <Ν寸.寸In s(No_ 寸 寸 (9·εοοΌΙ)ρρ 寸 8.εcn (3οοΌΙ)ρρ8//ε<Ν (Γ 寸)pootnl-fs价斗 φ^-奪 (8.Γ9·π)ρρ<Ν//ε (9,6^040 ρριη寸·ε (8·Γ9·6)ΡΗ6τ ^.6)+->6Ι·ε (9.6SCO寸· ε 9^9.6)305^ (9·6^ΊΪ)ρρ00ΐ·ε τ 寸 9 s 1314453
(96P0I.S (s)p I寸 (9·ι>t.6) PP 69.e (9·εΓΝΓ·6) PPCNJ寸·ε (寸·<N «5寸 t.6) PPP 9I.e (s^ln寸·£ (r6)m.£ soooo.e(s)mT (Γ6)Η9·ε (9CNT.6) ρρ ίοο.ε丨 (s)l £00·£(Γε - 596ΡΡΡ 96·ε - (9·卜)5寸·寸 丨 (96P9SW (<NI) poos_£ - (3Ι)ΡΛ9·ε (寸.<Νβ·ΙΙ)ρρ εζ/ε (寸.寸ricppcn卜.rn (81^9ΊΙ)ρρ049·ε (寸ciT-H)pp9t>.cn 寸ε τ -9二-窭 « 寸 e τ 餾替u -9 二-#< 9 9 1314453 s ss (9ίι)ρ<νατ (9·ιι)τ36Γε (9·6) P εο·寸 (9.6)p89.e 上05 Μ.ΐιζ.ς s s.e (9_I >_9)pp 寸ε·寸 (寸νοβΊϋιροοοβ (9·Ιΐ)ϋ s 52 (°19.6)书 90ΟΟ (°19·6)ρρ§ (5.6) ΡΡ ΙΟ·Α (<Ννο·6)+->ρ 9000
S900T (S6P 90.00 (5)105 (5) U9.卜 (S·卜rorA (S)P90.8 (5)Ρ3Γ8(s)i.A (5) 59.卜(sros (5) ρΓΝΙίοο (寸.8) P 66·卜 日Α寸.A 日19·卜 0 LVL (寸·8) P 66·卜 寸 εζ 73soldK3 3應 6 οο L 9 S 寸 ετ IT3ls-5-0Q^ 1314453
* 表2.1-5在CD3OD中的13C NMR光譜資料 碳 1α 2 3 4 5 糖部分 半乳糖-1 95.7 97.8 98.9 2 67.9 67.6 70.5 - 3 69.1 75.3 69.7 4 69.2 68.8 73.5 - - 5 68.7 72.0 71.4 - 6 64.3 62.4 62.1 - - 遠志醇-1 65.8 68.0 68.1 2 73.3 76.7 76.7 - 3 75.2 78.0 78.1 - - 4 80.3 72.0 71.9 - - 5 69.7 82.4 82.5 - - 6 61.0 63.1 63.1 _ 葡糖-1,6-二填酸 - - 93.9 103.2 2 - 73.6 79.2 3 - - 75.4 79.2 4 - - - 71.6 71.8 5 - - 75.2 78.5 6 - - - 62.7 63.1 果糖-1,6-二麟酸 65.6 - 2 - - - 105.3 - 3 - 80.6 - 4 - 74.4 - 5 - - - 84.7 - 6 一 63.6 23 1314453
apiose-l 彎 2 3 4 5 苷元部分 1 129.1 2 129.6 3 128.7 4 133.9 5 128.7 6 129.6 7 168.2 8 9 OMe - - - 110.9 78.6 - - 81.4 _ - - 76.1 _ - 66.9 131.2 131.4 122.8 134.9 130.9 130.8 133.6 108.5 129.5 129.6 115.4 154.7 134.3 134.4 165.8 135.5 129.5 129.6 115.4 154.7 130.9 130.8 133.6 108.5 168.7 167.9 167.7 132.0 - - 132.8 - - - 60.3 56.5 57.5 α在〇2〇中的記錄 圖式簡單說明 圖1顯示了根據本發明的化合物Μ的異核多鍵碳顧 關係圖谱（HMBC)相互關係，化合物h為從〜W 的根的水溶性萃取物純化得到。 圖2顯不了根據本發 人…碰βΗ〆， J化0物i-s的核-核過偶極你 口衫響關係（NOESY) ’化合物 為故 Polygala tenuifoil 的根的水溶性萃取物純化得到。 24
Claims (1)
1314453 十、申請專利範圍: ί公軎.本 (2009年7月修正) 1. 一種具有下式的遠志酚苷，
CHoOH 包括其光學活性的化合物的消旋混合物或光學純R和S立 體異構體， 其中R、R1和R”獨立地為11或尺1，前提是R、R/和Rn中只 有一個為R!，其中K為
其中R2為氫，或其可藥用鹽。 2. 如申請專利範圍第1項所述的遠志酚苷，其中R為Ri， R'和R"為Η，或其可藥用鹽。 3. 如申請專利範圍第1項所述的遠志酚苷，其中R|為Ri， R和R”為Η，或其可藥用鹽。 4. 如申請專利範圍第1項所述的遠志酚苷，其中R”為Rl5 R 和R1為Η，或其可藥用鹽。 5. —種使用如申請專利範圍第1至4項中任一項所述的遠 25 ‘1314453 (2009年7月修正) 志酚苷或其可藥用鹽於製造抗抑鬱藥物的用途。 6. —種使用如申請專利範圍第j 志酚苷或其可藥用鹽於製造用 甲腎上腺素重攝取來提供效果 7. 如申請專利範圍第6項中所述 至4項中任一項所述的遠 於治療一種可藉由抑制去 的疾病的藥物的用途。 的用途，其中所述的疾病 為成瘾性障礙、戒斷綜合症、適應性障礙、年齡相關的 認知障礙和精神障礙、神經性厭食症、情感淡漠、注意
力缺陷障礙、注意缺陷障礙多動症（ADHD)、雙相性精神 障礙或肥胖症。
26
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| US11857592B2 (en) * | 2020-12-14 | 2024-01-02 | Biolite, Inc. | Polygala extract for the treatment of attention-deficit hyperactivity disorder |
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